What is
the Fugu Genome Project?
The Fugu Genome Project is an international program aimed at determining
the complete DNA sequence of the genome of the Japanese pufferfish, Fugu
rubripes. Despite the obvious differences between fish and humans,
it is expected that comparisons of the human genome with that of Fugu
will shed light on the common genetic systems shared by these two animals,
and help us understand the information encoded in the human genome.

What is
Fugu?
Fugu is a teleost fish belonging to the order Tetra-
odontiformes (four toothed puffers) and a member of the gnathostomes (jawed
vertebrates). There are over 100 species of pufferfish with diverse salt
water and fresh water habitats. Fugu species are farmed in Japan and the
flesh is consumed as a delicacyalthough certain organs of the fish
must be avoided because they contain a potent neurotoxin.

What was
actually accomplished?
Today's announcement marks the completion of the draft sequence of the
Fugu genome. Over the past year, nearly four million pieces of Fugu genome
sequence were determined by the Fugu Genome Consortium. These genomic
fragments, averaging around 600 DNA bases in length, overlap each other,
which allows them to be reassembled computationally to reconstruct long
stretches of the Fugu genome, spanning tens of thousands of DNA bases
in length. Fugu is the first animal genome to be sequenced and assembled
in the public sector using this "whole genome shotgun" sequencing
approach.

Why is
this sequencing achievement important?
The Fugu genome is the first vertebrate genome to be draft sequenced after
human. Its compact form and similarity to the human genome will make it
an important tool for getting at the information encoded in the human
sequence. We now have in hand the basic gene-level description of two
vertebrates. Comparing and contrasting them will allow us to discover
new human genes and, importantly, elements which control or regulate the
activity of genes. Using genomes in this way has been compared to the
way in which ancient languages were decoded using the Rosetta Stoneone
common text translated side-by-side into different languages.

But I
thought all of the human genes were identified by now?
No. The computational methods for predicting genes are imperfect, and
we know that a significant number of human genes remain to be discovered
in the human genome sequence. Comparison between genomes is a powerful
way to find such genes. More significantly, there are no good computational
methods for reliably finding the elements which surround genes and control
their expression, that is, determine when and where a gene will be turned
on or off, and how much protein should be made. For example, genes that
are used in the kidney may not be used in the brain. We are still learning
to detect these genomic signals. This is an important missing piece of
the human genome puzzle.

So what
makes Fugu such a good choice for comparison with human?
First, Fugu is a vertebrate-despite their apparent differences, fish have
nearly all of the same organ systems and physiology as humans, in contrast
to the more distantly related invertebrate animals already sequenced,
like flies and worms. Just as important, however, is that the Fugu genome
is unusually small for a vertebrate. The pioneering work on Fugu, published
in the journal Nature in 1993, showed that despite a similar gene content,
the entire Fugu genome is only 1/8th the size of the human. Even among
fish, Fugu is special: most fish genomes are several times longer than
Fugu's.

How big
is the Fugu genome?
Pufferfish have the smallest known vertebrate genomes, around 350-400
million bases long, or 350400 megabases. (These bases are denoted
by letters  A, C, T, or G  which represent the chemical units
that are strung together to make genes and chromosomes.) Fugu has 22 pairs
of chromosomes, though these have no direct correspondence with the 23
pairs of human chromosomes. For comparison, the human genome is about
three billion bases long. Despite this size difference, however, both
Fugu and human are expected to have a similar repertoire of genes

How can
fish and humans have the same set of genes? Aren't they very different?
It depends on what you mean by "the same." It has been amply
demonstrated that many human genes including, for example, "disease
genes" like dystrophin, whose mutation causes muscular dystrophy,
have close relatives in Fugu. These related genomic features can be detected
computationally by comparing the two genomes and looking for similar sequences.
The Fugu and human genomes are similar by virtue of their shared vertebrate
heritage. Of course, humans (and Fugu) will have their own unique genes
that are special for human-ness and fish-ness that the genome comparisons
will also bring to light. But even these fish- and human-specific genes
are likely to share a common genetic heritage.

If they
have similar gene content, why is the Fugu genome so much smaller than
the human genome?
Genomes contain more than just genes. In fact, only a few percent of the
human genome actually represents "coding sequence," the functional
parts of genes. The rest of the human sequence is dominated by highly
repetitive non-gene DNA-for example, regions that read "ACACACAC
" for hundreds of bases, or have longer sequences that are
scattered throughout the human genome hundreds of thousands of times.
While these repeats make up 40% of the human sequence, the Fugu genome
has much less repetitive content-for mysterious reasons that should be
illuminated by the genomic sequence now in hand. But it's not only the
relative lack of repeats that makes Fugu special-Fugu genes themselves
are more compact than human genes, and packed more tightly on the genome.
This is the main reason Fugu was chosen for sequencing-as a cost-effective,
more-genes-for-the-buck shortcut to a vertebrate gene set, the gene-rich
Fugu can't be beat.

Why sequence
Fugu rather than another mammal like mouse or rat?
Genome sequencing shouldn't be thought of as an either-or proposition.
It is essential that a broad range of animal genomes be sequenced, to
shed light on the underlying similarities and essential differences between
species. Fugu is just the beginning. The ongoing mouse and rat genome
projects are critical for biomedicine, and will be particularly powerful
tools because these animals are mammals (more closely related to human)
and can be bred and studied more easily than Fugu. The Fugu genome provides
a more distant evolutionary comparison (400 million years, versus 100
million years for mouse and rat) that permits a more accurate triangulation
of genome function than mouse or rat alone. Genomic features that are
common to Fugu, rodents, and human will focus our attention on the essential
core genes that define being a vertebrate.

How are
Fugu and humans related by evolution?
About 450 to 500 million years ago, the first vertebrates (animals with
segmented backbones made of cartilage or bone) appeared in the early oceans.
Their descendents split into two main groups: the ray-finned fishes-which
include Fugu and most fish familiar to us from the dinner table-and the
lobe-finned fishes, a more obscure group with fleshy paddle-like appendages
in place of the paper-thin fins of the ray-finned fish. Over millions
of years, these lobe-fins evolved into the limbs possessed by all four-limbed
creatures (the tetrapods, including reptiles, amphibians, birds, and mammals).
So Fugu are our very distant cousins, sharing a common ancestor with us
nearly half a billion years ago. Remarkably, this common ancestry is still
recorded in our genes.

Where
can I learn more about the Fugu and its genome?
Below are a few of the key scientific publications which describe landmarks
in the work on Fugu:

The U.S.
Department of Energy Joint Genome Institute
The Department of Energy's Joint Genome Institute, established in 1997,
is one of the largest publicly funded human genome sequencing institutes
in the world. The JGI was founded by the three University of California-managed
national laboratories: Lawrence Berkeley National Laboratory and Lawrence
Livermore National Laboratory in California and the Los Alamos National
Laboratory in New Mexico. The JGI is led by Dr. Trevor Hawkins and has
its main headquarters and Production Genomics Facility in Walnut Creek,
California. The JGI employs about 240 full-time people and has programs
in genomic sequencing, computation, functional genomics, genomic diversity
and new technology development. In its role as a partner in the Human
Genome Project, JGI was responsible for sequencing human chromosomes 5,
16, and 19, which make up 11% of the human genome. Funding for the JGI
is predominantly from the DOE Office of Science with additional funding
from NIH, NSF, USDA and NASA. Information about the JGI can be found on
the genome portal at www.jgi.doe.gov.

Institute
of Molecular and Cell Biology (IMCB)
IMCB was established in 1987 at the National University of Singapore (NUS).
Its mission is to develop and foster a vibrant research culture for biological
and biomedical sciences which will support the development of biotechnology
for the human health care industry in Singapore. IMCB is one of the 5
biomedical sciences research institutes funded by the Biomedical Research
Council. From a modest start with 38 scientists it today has a research
staff of 250. These comprise an internationally diverse group representing
Asia, North America, and Europe. Their research focuses on cell regulation
and signal transduction, development, functional genomics, immunology,
virology, infectious diseases and drug discovery. The IMCB has established
collaborations with industry, universities, and research institutions
worldwide. imcb.nus.edu.sg

The Singapore
Biomedical Research Council (BMRC)
is part of the National Science and Technology Board (NSTB), Singapore's
national agency for science, technology and research. BMRC oversees and
provides support to public sector biomedical research and development
activities in Singapore. The Council also aims to strengthen collaborative
public research in the biomedical sciences in Singapore. The Council's
objectives are to support, sustain and stimulate excellent research for
maintaining and improving human health, train people in high quality research
skills to meet Singapore's needs of health, quality of life and global
economic competitiveness, and promote societal awareness of biomedical
research. www.biomed-singapore.com

The Medical
Research Council (MRC)
is a national organization funded by the United Kingdom taxpayers.
Its business is medical research aimed at improving human health. The
research it supports and the scientists it trains meet the needs of the
health services, the pharmaceutical and other health-related industries
and the academic world. MRC has funded work which has led to some of the
most significant discoveries and achievements in medicine in the UK. About
half of the MRC's expenditure of £345 million is invested in over
50 of its Institutes and Units, where it employs its own research staff.
The remaining half goes in the form of grant support and training awards
to individuals and teams in universities and medical schools. www.mrc.ac.uk

The Cambridge
University Department of Oncology, United Kingdom,
hosts the Cancer Genomics Program, a multdisciplinary group of investigators
in areas ranging from comparative genomics, genetics, cell biology and
translational clinical research, to address basic and translational research
questions applicable to the understanding of cancer. The University of
Cambridge is one of the oldest universities in the world, and one of the
largest in the United Kingdom. It has a world-wide reputation for outstanding
academic achievement and the high quality of research undertaken in a
wide range of science and arts subjects. The University's achievements
in the sciences can be measured by the sixty or more Nobel Prizes awarded
to its members over the years. www.hutchison-mrc.cam.ac.uk

The Institute
for Systems Biology
located in Seattle, Washington, was co-founded in 2000 by Lee Hood,
Ruedi Aebersold, and Alan Aderem as a private, non-profit research institute
devoted to systems biology, an emerging field made possible by rapid advancements
in genomic, proteomic and computer technologies. Unlike traditional scientific
approaches that examine single genes or proteins, systems biology focuses
on studying the complex interaction of vast numbers of biological elements.
The Institute is also pioneering new science education and increasing
public awareness of biotechnology issues. www.systemsbiology.org/The Celera Genomics Group
headquartered in Rockville, MD, is engaged principally in integrating
advanced technologies to create therapeutic discovery and development
capabilities for internal use and for its customers and collaborators.
Celera's businesses are its online information business and its therapeutics
discovery business. The online information business is a leading provider
of information based on the human genome andother biological and medical
information. Through the therapeutic discoverybusiness, Celera intends
to leverage its genomic and proteomic capabilities to identify drug targets
and diagnostic marker candidates, and to discover novel therapeutic candidates.
www.celera.com

Myriad
Genetics, Inc.
is a leading biopharmaceutical company focused on the development
of novel healthcare products. Based in Salt Lake City, Utah, the company
has established two wholly owned subsidiaries. Myriad Pharmaceuticals,
Inc. develops and intends to market therapeutic products, and Myriad Genetic
Laboratories, Inc. develops and markets proprietary predictive medicine
and personalized medicine products. The company has established strategic
alliances with Bayer, Eli Lilly, Hitachi, Novartis, Oracle, Pharmacia,
Roche, Schering AG, Schering-Plough and Syngenta. www.myriad.com